Uiiilcu



SUBSTITUTED Z-PHENOTHIAZINYL TRIFLUORG- h IETHYL KETONES William H. Edger-ton, Strafiord-Wayne, Pa., assignor to Smith Kline & French Laboratories, Philadelphia, Pa., a corporation of Pennsylvania No Drawing. Filed May 23, 1958, Ser. No. 737,190

12 Claims. (Cl. 2'60243) This invention relates to novel IO-(dialkylaminoalkyD- 2-phenothiazinyl tritiuoromethyl ketones useful as therapeutic agents. Further, this invention relates to the novel 2-phenothiazinyl trifluoromethyl ketone having utility as an intermediate.

The compounds of this invention are useful, specifically, as tranquilizers, antiemetics, calmatives, antihistaminics and antispasmodics. In addition, these compounds have chemotherapeutic activity, such as antibacterial and fungicidal activity.

The IO-(dialkylaminoalkyl)-2-phenothiazinyl trifluoromethyl ketones of this invention are represented by the general formula:

FORMULA I droxyalkylene) -piperaziny1, N-(w-alkanoyloxyalkylene piperazinyl, N-(w-benzoyloxyalkylene)-piperazinyl, N- (w hydroxyalkyleneoxyalkylene) piperazinyl, N (walkanoyloxyalkyleneoxyalkylene) piperazinyl, N (w benzoyloxyalkyleneoxyalkylene)-piperaziny1, N-phenylalkylpiperazinyl, N-dialkylaminoalkylenepiperazinyl, or N-acylpiperazinyl, for example N-alkanoylpiperazinyl or N-benzoylpiperazinyl.

By the term alkyl where used herein, aliphatic groups having not more than 4 carbon atoms and preferably not more than 2 carbon atoms are indicated. The term alkylene, used in connection with a carbon chain, unless stated otherwise represents aliphatic groups vof from 2 to 4 carbon atoms and preferably an ethylene group.v

The term alkanoyl is used to represent an aliphatic acyl group having not more than 4 carbon atoms and, preferably, not more than 2 carbon atoms.

The advantageous compounds of this invention are represented by the following formulas:

FORMULA II 5 N-(w-hydroxyalkylene)-piperazinyl,

2,944,053 Patented July 5, 1960 when A represents a divalent, straight or branched alkylene chain containing 2 to 4 carbon atoms, separating the nitrogen atoms by at least 2 carbons; and Z rep resents dimethylamino, piperazinyl, N-alkylpiperazinyl,

N-(w-alkanoyloxyalkylene)-piperazinyl, N-(w-benzoyloxyalkylene)-piperazinyl, N (w-hydroxyalkyleneoxyalkylene)-piperazinyl, N-(w-a1kanoyloxyalkyleneoxyalkylene) -piperazinyl or N (w-benzoyloxyalkyleneoxyalkylene)-piperazinyl.

Preferred compounds of this invention are represented by the following formula:

ice

FORMULA HI s t \N C-CF| JJHr-iH-CHr-Z 2-5 droxyethoxyethyl)-piperazinyl or N-(w-acetoxyethoxyethyl) -piperazinyl.

This invention also includes salts of the above defined bases formed with nontoxic organic and inorganic acids. Such salts are easily prepared by methods known 39 to the art. The base is reacted with either the calculated include moieties such as N-alkylpiperazinyl, N-(w-hyamount of organic or inorganic acid in aqueous miscible solvent, such as acetone or ethanol, with isolation of the salt by concentration and cooling or an excess of the acid in aqueous immiscible solvent, such as ethyl c ether or chloroform, with the desired salt separating directly. Exemplary of such organic salts are those with maleic, fumaric, benzoic, ascorbic, parnoic, succinic, bismethylenesalicylic, methanesulfonic, ethanedisulfonic, acetic, propionic, tartaric, salicylic, citric, gluconic, lactic, malic, mandelic, cinnamic, citraconic, aspaztic, stearic, palrnitic, itaconic, glycolic, p-aminobenzoic, glutamic, benzene sulfonic and theophylline acetic acids as Well as with the 8-halotheophyllines, for example, 8-bromotheophylline. Exemplary of such inorganic salts are those with hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric and nitric acids. Of course these salts also may be prepared by the classical method of decomposition of appropriate salts which is well-known 5D to the art.

The novel 2-phenothiazinyl trifluoromethyl ketone (Formula IV) is used as an intermediate to prepare the pharmacologically active IO-(dial-kylaminoalkyl)-2-phenothiazinyl trifiuoromethyl ketones represented by For- 5 mula I. In general, the preparation is carried out according to the following synthetic procedure:

FORMULA IV Where used herein, the term dialkylaminoalkyl represents aliphatic-aminoalkyl groups, such as dimethylaminoalkyl, and nitrogen-containing heterocyclicealkyl groups, such as morpholinoalkyl.

2-phenothiazine, trifluoromethyl ketone, used as an in,-

halic acid-formed during the reaction.

. '3' termediate as shown above, is readily prepared by the cyclization of appropriately substituted acetophenonesz- I? .-o.--ort -GE-CFa'. X- HzN. N E

X' represents-chloro, bromo or iodo.

'This method. is carried out by heating the. above acetophenones, in the presence of an acid-binding agent, present in an amount sufiicient to neutralize the hydro- Exemplary of such acid-binding agents are the-alkali'carbonates, .such as sodiumcarbonate, sodium bicarbonate or preferably 7 .potassium carbonate. The reaction is run in a suitable;

nonreactive organic solventain. which the reactants are at least partially soluble. are dioxane, dimethylaniline; diethylformamide, methylformarnide, dimethyl formamide, or dimethylacetamide. Preferably, the solvent is dimethylformamide and other 7 similar lower-carbon amides-.1

Optimum yieldsvareobtained..when catalytic amounts of copper or copper-bronze powder are added, for instance up to by weightot the acetophenone. The reaction mixture isadvantageously heated at from about lOOfto. 220 C..for longperiods, such'as from4to 60 hours. Preferably, the reaction mixture is heated. with stirring ,atthe boiling point of the solvent for from 8 'to 24hours. The reaction mixture is worked upby cooling,

filtering and quenching in water. The separatedproduct is washed,'recrystallized and,optionally, sublimedtogive the desired 2-phenothiazinyl trifiuoromethyl ketone.

The substituted acetophenones are prepared by meth-. odsianalogous to those in the prior art. For instance, 4-chloro-3nitro-a,u,a-trifiuoroacetophenone is condensed with o=bromothiophenol under alkaline conditions to give Exemplary of such solvents V than one equivalent of sodium or potassium amide in refluxing benzene or toluene for from minutes'to 12 hours, preferably one to eight hours.

7 The IO-(dialkylaminoalkyl)-2-phenothiazinyl trifluoro methyl ketone is preferablyisolated by quenching the cooled reaction mixture withwater and extracting the separated organic layer .Withdiluteacidfpreferably dilute:

hydrochloric acid. The acid ex-tracts are combined, neutralized carefully with, dilute. alkali such ..as.sodium. bl?

carbonateand extracted with-benzene. Thedriedbem zene extracts are evaporated and the residue :fractionally distilled under high vacuum to give the oily base which is conveniently converted into'a stable salt byreaction with a suitable organic or inorganic acid.

The 10-(m-piperazinylalkyl) -2-phenothiazinyl trifluoromethyl ketonesv are: prepared advantageously by. alkylating Z-phenothiazinyl trifiuoromethyl ketone, with an. -w-

haloalkylpiperazinehaving the. free N-hydrlo'gen-softhe.

piperazinyl moiety replaced by; an easily removed. moiety,

for example a carbethoxy or, preferably,.formylgroup. TheN-protective group isrthen, removed under very mild conditions, such as. by weakly alkaline, hydrolysis. The resulting. 10-.(w-piperazinylalkyl)-2-phenothiazinyl. trifluoromethyl ketones. are. then further ,alkylatedto form; modifications corresponding to various substituted piper..- azinyl moieties as previously. defined herein Such methods of alkylationare by a reactive ester .suchas. an alkyl.

halide in the presence of an' acid-bindingagent; as..d.e:

scribed above, in an inertisolventasuch as benzene or xylene, or by reaction with an alkylene oxide, such as ethylene oxide in a lower alcohoL. In addition, l0-(N'- alkyl N piperazinylalkyl) 2 phenothiazinyl trifluoro-- methyl ketones having a terminal group on the N'-alkyl moiety capable of .undergoingufurther reaction, such as 4-(2'-bromophenylmercapto) -3.-nitro u,a,m' trifluoroace tophenone. The 3-nitro'groupis reduced with stannous chloride-hydrochloric acid to give 3-amino-4-'(2-bromo; phenylmercapto) -u,oz,a trifluoroacetophenone .which' 'is' then further reacted as described'above.

The 4-halo-3-nitroa,u-trifluoroacetophenones, used as described above, are similarly prepared by' methods analogous to those the priorart; Forinstance, chloro benzene is treated with trifluoroacetyl chloride ina typical Friedel-Crafts reaction to give 4-Chl0IO-a,oz,u-tI'i-' fluoroacetophenone which is nitrated with a mixture of' nitric acid or potassium nitrate and sulfuric acid to yield the desired compound. Alternatively, 4,a,a,u-tetrachloroacetophenone is converted by means of antimony trifluoride to the a,a,u-trifluoroacetophenone derivative which in turn is nitrated to give 4-Cl'l101'O-3- flitI0-cc,cc,atrifiuoroacetophenone.

The intermediate Z-phenothiazinyl trifluoromethyl 'ketone is alkylated with a reactive dialkylaminoalky-l drides, preferably-"sodium hydride oralkali metal aryl or alkyl compounds, preferably phenyl or octyl sodium.

' If an acid addition salt of the reactive dialkylaminoalkyl ester. isvused, a corresponding increase in the-amount; of

. acidsbindingv agent; must be used;

The preferred. method of alkylation, -however,.. is to' react 2-phenothiazinyl trifluoromethyl ketone with: a, dialkylaminoalkyl chloride or bromide-withslightly less r l-hydroxyalkyl, are optionally reacted with an ester such as an acyl halide in the presence of an acid-binding agent to give, for example, N acyloxyalkyl derivatives of 10- (o-piperazinylalkyl) -2-phenothiazinyl trifluoromethyl ketones.

Although 2-phenothiazinyl trifluorometh'yl: ketone is quite stable, in prolonged contact with aqueous alkali-it does have some tendency to undergo ahaloform reaction. if this is the case under, certain=reaction conditions; the keto group can be protected by forming a k'eta1 compound, preferably with ethyleneglycol, performing the desired reaction and. thenremoving the protective group by brief treatment with acid. .The foregoing is.a generaldescription ofstheimainusynthetic. routes. inzthe preparation of. .10- (dialkylaminoab...

kyl) .-2-phenothiazinyl' .trifiu'oromethyl ketone derivatives.

It will. be readily apparent:totoneiskilled --in the. artsthatvariations of;.these=procedures are possibleu. Of'particue lar advantage as ,a.preparative1procedure isr the-:.method thoroughly discussed. above;v namely N-alkylation; 0L2.- phenothiazinyl trifiuoromethyl ketone in the;10 position of the phenothiazine-ring-byareactive diallylaminoalkyl ester. V

It will be readily apparent to ,one sldlledrincthe-art that certain of thercompounds'of this'invention,1notably A suitable acidthose in which A- isrepresentedabyan aliphaticgcarbon chain, branched-.so that; an. asymmetric carbon atom. is formed, may be present as optical isomers. The 'connotaa tion ofthe generalformulae-presented herein isztoinclude all isomers, particularly" the-a separated: d1;.0r:; [optical isomersas wellase-theadl mixturesofqthese isomers;v If

desired, the isomers-may be separatedrforindividuakuse by. separatiommethods known to the art, such as .frac- I tio'nal crystallization, iforlins tancQ-of the *d-tartarate salts of the l0-(dialkylaminoalkylI-Z-phenbthiazinyl trifluoromethyl ketone derivativesr" Alternatively, starting with an optically active side/chain desired optical isomer.

The following examples are not limiting but are illustrative of compounds of thisinventionand the procedures for theirpreparation and serve to make fully appar- 7' a synthesis may yield' the cut all of the compounds embraced by the general formula given above and the preparation thereof, respectively.

Example 1 A stirred suspension of 67.5 g. of chlorobenzene and 80.0 g. of aluminum chloride is cooled to 10 C. and 66.3 g. of .trifluoroacetyl chloride is added. =When the addition is complete, the mixture is allowed to stand at room temperature overnight. The reaction mixture is then poured onto ice and water, and extracted with ether. The dried ether extracts are evaporated to give 4-chlorou,m,a-trifluoroacetophenone.

A mixture of 31.5 g. of concentrated nitric acid and 49.0 g. of concentrated sulfuric acid, cooled to C., is added slowly to 20.8 g. of 4-chloro-a,a,a-trifluoroacetophenone. The mixture is stirred for three hours at C. and then poured onto ice. The solid is filtered, washed with Water and recrystallized to yield 4-chloro-3-nitroa',u,a'-trifluoroacetophenone.

A solution of 25.3 g. of 4-chloro-3-nitro-a,a,a-trifluoroacetophenone in 250 ml. of ethanol is added to a mixture of 4.0 g. of sodium hydroxide in 25 ml. of water and 18.9 g. of o-bromothiophenol in 300 m1. of ethanol. The suspension is refluxed for one hour and filtered hot. The filtrate yields 4-(2-bromophenylmercapto)-3-nitro-u,a, xtrifluoroacetophenone upon dilution with a small amount of water and cooling.

A solution of 112.8 g. of stannous chloride crystals in 300 ml. of concentrated hydrochloric acid is carefully mixed with 20.3 g. of 4(2'-bromophenylmercapto)-3- nitro-a,a,a-trifiuoroacetophenone. The mixture is stirred and refluxed for three hours. The cooled reaction mixture is made alkaline, refluxed for 30 minutes and then extracted with benzene. The solvent is removed by distillation in vacuo and upon purification of the residue, 3- amino 4 (2' -bromophenylmercapto) a,a,a t1ifluoroacetophenone is obtained.

A suspension of 18.8 g. of 3-amino-4-(2'-bromophenylmercapto) u,a,oc trifluoroacetophenone, 7.3 g. of anhydrous potassium carbonate and 0.7 g. of copperbronze powder in 175 ml. of dimethylformamide is heated at reflux with stirring for 15 hours under a stream of nitrogen. The cooled reaction mixture is filtered and the filtrate diluted With water. The solid which thus forms is vacuum sublimed and recrystallized to give pure 2 -phenothiazinyl trifluoromethyl ketone.

Example 2 A mixture of 29.5 g. of 2-phenothiazinyl trifluoromethyl ketone (prepared as in Example 1) and 2.2 g. of lithium amide in 100 ml. of dry xylene is refluxed for 15 minutes. A solution of 12.7 g. of 3-chloro-1-dimethylaminopropane in 20 ml. of xylene is then added slowly and the mixture refluxed for three hours. The cooled reaction mixture is treated with water, extracted with dilute hydrochloric acid and the acid extracts neutralized with dilute aqueous sodium bicarbonate. After benzene extraction and subsequent removal of the dried solvent in vacuo, the residue is crude -(3'-dimethylaminopropyl) 2 phenothiazinyl trifluoromethyl ketone.

Treating an ethereal solution of the free base (1.0 g. in 75 ml. of ether) with ethereal hydrogen chloride yields the hydrochloride salt.

Example 3 A mixture of 29.5 g. of 2-phenothiazinyl trifluoromethyl ketone (made as in Example 1), 3.7 g. of sodium amide and 300 ml. of xylene is refluxed with stirring for 20 minutes. A solution of 18.5 g. of 1-(3-chloropropyl)-4-niethylpiperazine in 100 ml. of xylene is added and the mixture refluxed for four hours. Working up the reaction mixture as described in Example 2, gives the product, 10 [3 (4" methyl 1" piperazinyl)- propyll-z-phenothiazinyl trifluoromethyl ketone.

Example 4 A suspension of 14.8 of 2-phenothiazinyl trifluoromethyl ketone (prepared as in Example 1) and 1.8 g. of sodium amide in 200 ml. of xylene is heated at reflux with stirring for 20 minutes. A solution of 10.0 g. of lformyl-4-(3'-chloropropyl)-piperazine in 30 ml. of xylene is added and refluxing continued for four hours. The reaction mixture is treated with water and the xylene layer extracted with dilute mineral acid. The acid extracts are made basic with dilute sodium bicarbonate solution and extracted with benzene. Evaporation of the solvent in vacuo yields the product, 10-[3(N-formylpiperazinyl) propyl] 2 phenothiazinyl trifluoromethyl ketone.

A solution of 89.8 of the ketone in 500 ml. of ethanol and 300 ml. of water containing 20 ml. of 40% sodium hydroxide solution is refluxed for 30 minutes. The ethanol is distilled-01f in vacuo on the steam bath and the residue is treated with benzene and water. The dried benzene layer is evaporated in vacuo to give 10,-(3'-piperazinylpropyl) 2 -phenothiazinyl trifluoromethyl ketone.

Example 5 Ethylene oxide (0.444 g.) is added to a solution of 4.2 g. of 10-(3-piperazinylpropyl)-2-phenothiazinyl trifluoromethyl ketone (prepared as in Example 4) and the resulting mixture refluxed for two hours. Removal of the solvent in vacuo yields the residual product, l0-[3- (N-hydroxyethylpiperazinyl) -propyll -2-phenothiazinyl trifluoromethyl ketone.

A solution of 2.3 g. of this ketone and 0.5 g. of acetyl chloride in ml. of benzene is heated at reflux for 20 minutes and cooled. Evaporation of the solvent in vacuo gives the monohydrochloride salt of 10-[3'-(N- acetoxyethylpiperazinyl) -propyl] -2-phenothiazinyl trifluoromethyl ketone. This is dissolved in alcohol and treated with alcoholic hydrogen chloride. and cooling yields the dihydrochloride salt.

Similarly, 10- [3- (N-hydroxyethylpiperazinyl) -propyl] 2-phenothiazinyl trifluoromethyl ketone is reacted in ben zene solution with propionyl chloride (0.54 g.) to yield 10-[3(N-propionyloxyethylpiperazinyl)-propy1l 2 phenothiazinyl trifluoromethyl ketone hydrochloride.

In the same manner, reaction with benzoyl chloride (0.8 g.) in benzene yields the hydrochloride salt of 10- [3'- (N-benzoyl-oxyethylpiperazinyl) -propy1] -2-phenothiazinyl trifluoromethyl ketone.

Example 6 v A suspension of 29.5 g. of Z-phenothiazinyl trifluoromethyl ketone (prepared as in Example 1) and 2.2 g. of lithium amide in ml. of dry xylene is stirred and refluxed for 20 minutes. A solution of 14.2 g. of 1- chloro-3-dimethylamino-2-methylpropane in 30 ml. of xylene is added and the resulting mixture heated at reflux for three hours. The reaction mixture is cooled, treated with Water and extracted with dilute hydrochloric acid. The acid extracts are neutralized with'dilute sodium bicarbonate solution and extracted with benzene. Removal of the dried solvent gives 10-(3'-dimethylamino- 2-methyl-propyl)-2-phenothiazinyl trifluoromethyl ketone.

The free base (1.0 g.) is dissolved in 100 ml. of ether and treated with an excess of alcoholic hydrogen bromide to separate the hydrobromide salt.

Example 7 chloric acid, The. extractsjare neutralized with dilute Concentration enesali'cylate-salt: I

fluorometh'yl ketone,

sodium bicarbonate solution .andthen extracted. with benzene. 'Removal of the,..dried,solvent gives the product', I (2f N inorpholinylethyl)-2-phenothiazinyli trifluore-.methylketone.'

A solution of 1.0g. of the free base in 100 ml. of ethyl acetate is-treatedfivithanexcess of'alcoholic maleic acid to 'give the 'maleate saltupon' concentration and cooling.

V Example-8; r V p A mixture-of 14.8 r g.- of 2-phenothiazinyl trifluoromethyl ketone (madeas in 'Examplel), 1.8 g.-of 'sodiunramide and10.;9 g of; 6-bromo-1-diinethylaminohexane in 100 ml. of 1 dfy-lxyle'ne 'isheated at reflux; for-eight hours. Tre at- V ing thereaction-mixtureasin-Example 2. gives -l0-'(6'- dimethylaminohexyl) 2-phenothiazinyl trifluoromethyl-ketone.

Theresidue is dissolved in ethyl'acetate and reacted with bismethylenesalieylic" acid to; yield the bis-methyl Example 4 9 Ajsuspe'nsion o;14.8 g..of 2-phenothiazinyli'trhluoro methyl"ketone (prepared as in Example 1) and 1.8g. of sodamide in 75 ml. of dr yxylene-is stirred while asolution of..:10-.8.g,jof 3-bromo-l-piperidylpropane. in 100ml. of: xyleneaisgadded. slowly at 100. C. The mixtureis refluxed for three.hours,.cooled and treated with water. 'The separated organic layer is.extractedwith.dilutehydrochloric acid,,:neutralized..with dilute aqueous :sodium bicarbonateand further. extractedwith benzene. Removal of the solvent in' vacuo gives 10-(3'-N-piperidylpropyl)-2- phenothiaziny-l trifluoromethyl ketone. V

Example 1 2A stirred suspension of 2.9 p of 2-phenothiazinyl trifluoromethylketone (madeas in Example 1) and 0.37 g. ofsodamide in 50 ml. of xylene. is refluxed While 2.9 g. of 3-.bromo-l-pyrrolidinylpropane hydrobromideis added. The resulting mixture is then stirred and refluxed for eight hours; Workingup as in Example v2, 10-(3'-N pyrrolidinylpropyl)-2-phenothiazinyl trifluoromethyl ketone is obtained.

Treating. an etherealsolution-of the free base with glacial acetic acid furnishes the. acetate salt.

Example] 1 7 'A. mixture of "4.2 g. of 10 (3'-piperazinylpropyl)-2 phenothiazinyl' trifluoromethyl' ketone .(made as. .in 'Example 4) 1.6 g. of w-brornobutanol and'1.5 g; of potassium carbonate in 200 ml. of. xylene is stirred and refiuxedsfor five. hours. After addition. of water to the reaction mixture, the separated xylene layer is extracted with dilute mineral acid. The acidextracts are neutrallZd"Wlfl1 dilute sodium. bicarbonate solution and extractedawith benzene. Distillingthe solvent in vacuo leaves; the-residual product, 10-[3-(N-w-hydroxybutylpiperazinyl)-propyl]-2 phenothiazinyl trifiuoromethyl ke- Example 7 12 V Amixtureof 1.4.8. g.;of 2-phenothiazinyltrifluoromethyl ketone(made asin' Exanrple l) and 1.8 g.-of'sodam ide m lon; rnlrof'dry xylene is stirred andrefluxed while'a solution of 9l4 g; of 3-chloro -l-(N-thiomorpholinyl)- propanein-50jml of xylene is added. The resulting mixture is; heated atreflux'for'seven hours. 7 th'eereaction mixture as outlined in- Example 2 results plienothiazinyl trifluoromethyl. ketone.

in" the. isolation of 1O-[3-(N-thiomorpholinyl)-propyl]-2f Working up 7 Example A- mixtu're of 14.8'-g. -1of 2 phen'othia'zinyl -trifluoro=j methyl ketone (prepared as in Example 1), 1.8 gi o'f sodamide and 10.0 g. of 3-ehloro-2-methyl-1-(N methylpiperazinyD -propane'in 150 ml. of'drybenzene is heated at refluxfor sixhours. Treating the reaction mixture? as described in Example 2 gives l0-[3-(4-'-me thyl-1.- piperazinyl) -2'-methylpropyl] -2-pl 1enothiazinyl trifluoroe methyl ketone; A solution of the free .base (1 .0 g.) in, 169 ml. of ether is treated with an excess of. alcoholic hydrogen chlorideto give thedihydrochloride salts.

Example '1 I A mixture of 14.8 g. .of 2-phenothiazinyl uifih fa V T methyl ketone (made as in-Example 1), 1.8g. of sodarni de 1: and 13.2 g. of 3-chloro-1-(N-benzylpiperazinyl) -propane in 150 ml. of toluene-is heated at reflux forseven hours.;

After treatingthe' reaction mixturelwith. water, "the sepae, I 7

rated organic layer is extracted ithdilute-hydrocmoric.

acid. The. acid extracts are .neutralized with dilute sodium bicarbonate solution and extracted withlbenzene Thesolventis removed -to'giveg the residual;.l0 [3.' (N-} methyl ketone. The .free-base-is reacted with-maleicI acid V inethyl acetate to furnish the dimaleatesalt.

Similarly, by using- 15.4 g; oi-.3-chloro-l (-N w-phenylbutylpiperazinyl)-propane, 10-[3'-(N-w-phenylbutylp@erazinyl) -propyll -2-phenothiazinyl trifluoromethylketone. is

obtained. ,7 V

Example "15 7 'To a' solution or 4.2 g. of 10- s' i erazinylpropyl) I 2-phenothiazinyl tn'fiuoromethyl ketone (prepared'as in Example 4) in'150 'mlfof benzene and 5 mliof'pyridine is added 4.8 -ml.'of' acetic anhydrid eywitlf swirling." After? standing overnight the reaction mixture lSj'WHSliBdfWlflli water-and'evaporated; solution of the residuejiri -al V cohol is reacted with one equivalent of hydrochlorio'acidi to yield 10-[3'-(-N-acetylpiperazinyl)-propyl]=2-pheno V thiazinyl trifluoromethyl ketone hydrochloride; 3

I Example 16 v p A'mixture of 4.2' g. of 10-(3' piperazinylpropyl-) 2 V phenotbiazinyl trifluoromethyl ketone-(made as-in Ex ample 4) in 150 ml. of benzene"and-'2;0 g: of benzoyl chloride is heated at reflux for-three hours: Concen i trading the reaction mixture yields-the solid"product;' 10-[3-(N-benzoylpiperazinyl) propyl]-Z-phnothiazinyl- 1 trifiuoromethyl ketone hydrochloride.

Example 1 A suspension of 4.2 g. of l0-(3'-piperazinylpropyl) 2-phenothiazinyl trifluoromethyl ketone (prepared' as. in Example 4), 1.8v g. ofv 2-bromo-2-hydroxyethyl ether and 1.3 g. of potassium carbonate in 150 of 'toluene' is refluxed for six hours. The reaction mixture is treated with' water, the organic layer separated and extracted withdilute. hydrochloric acid and neutralized with'dilute;

sodium bicarbonate solution. 'Extraction with benzene and subsequent evaporation of the solvent yields IO-IS Q (N-hydroxyethoxyethylpiperazinyl) propyl] '2 1 'pheno: thiazinyl trifluoromethyl ketone Q V 7 'Example 18 W H U 'To a solution of 5.1 g. of lQ-[3-(N-'hydroxyethoxyethylpiperazinyl) propyl] Z-phenothiazinyl trifluoromethylketone (made-as in Example 17) in.;100:;ml.,of

. benzene is added LO-g. of acetyl chlorideandgth'eareaction mixture allowed to standiat roomtemperaturef or 2.4- hours; The reaction mixture is poured .into; ;water;- V

neutralized with dilute sodium bicarbonate solutiomflnd.

extracted with benzene. Evaporation of the solvent leayesi the crude product, 10-[3T-(N-acetoxyethoxyethylpjper azinyl -propyll-2-phenothiazinyl' trifluoromethyl ketone;

Simlarly, acylating with benzoyl chloride. (2, 0. g;. r V

"nun-n...-

9. above, 10 [3-(N benzoyloxyethoxyethylpiperazinyl)- propyl]-2-phenothiaziny1 trifluoromethyl ketone is isolated.

Example 19 A mixture of 29.3 g. of 2-phenothiazinyl trifluoro-.

methyl ketone (prepared as in Example 1), 14.9 g. of 3-ch1oro-l-diethylaminopropane and 3.7 g. of sodium amide in 150 ml. of dry xylene is refluxed for. three hours. Working up the cooled reaction mixture as in Example 2, yields l-(3-diethylaminopropyl)-2-phenothiazinyl trifluoromethyl ketone.

The free base is readily converted to the hydrochloride salt by treatment with anhydrous hydrogen chloride in ether solution.

Example 21 A mixture of 4.2 g. of 10-(3'-piperazinylpropyl)-2- phenothiazinyl trifluoromethyl k'etone (prepared as in Example 4), 1.8 g. of l-iodobutane and 1.4 g. of potassium carbonate in 100 ml. of toluene is stirred and heated at reflux for four hours. The reaction mixture is filtered and the filtrate washed with water, dried and concentrated. The residue is dissolved in ethyl acetate and treated with two equivalents of maleic acid to give the dimaleate salt of 10- [3'-(N-butylpiperazinyl) -propyl] -2-phenothiazinyl trifluoromethyl ketone.

Example 22 A suspension of 4.2 g. of 10-(3'-piperazinylpropyl)- Z-phenothiazinyl trifluoromethyl ketone (prepared as in Example 4), 2.3 g. of 4-bromo-4-hydroxybutyl ether (prepared by the careful treatment of 4,4'-dihydroxybutyl ether with one equivalent of hydrobromic acid) and 1.4 g. of potassium carbonate in 150 ml. of xylene is refluxed for ten hours. Treating the reaction mixture as described in Example 17 yields 10-[3'-(N-hydroxybutoxybutylpiperazinyl)-propyl] 2 phenothiazinyl trifiuoromethyl ketone.

A solution of 5.6 g. of the free base in 75 ml. of benzene is treated with 2.0 ml. of butyryl chloride. After standing at room temperature for 12 hours, the reaction mixture is poured into water, neutralized with dilute sodium bicarbonate solution and extracted with benzene. Evaporation of the solvent leaves a residue which is dissolved in alcohol and reacted with anhydrous hydrogen chloride gas, thus yielding the dihydrochloride of 10-113- (N-butyryloxybutoxybutylpiperazinyl) propyl] -2-phenothiazinyl trifluoromethyl ketone.

What is claimed is:

1. Chemical compounds of the class consisting of a free base and its nontoxic organic and inorganic acid salts, the free base having the formula:

E CF: 2 9 I 1 in which A is an alkylene chain having 2 to 6 carbon atoms, separating the nitrogens to which it is attached eneoxyalkylene) piperazinyl, N (10,- benzoyloxyalkyleneoxyalkylene) piperazinyl,. N. phenylalkylpiperan'n' yl, N diethylaminoethylpiperazinyLN acetylpiperazinyl and N benzoylpiperazinyl; each' of the aforesaid alkyl moieties having 1 to 4 carbon atoms; each of the aforesaid alkylene moieties having 2- to 4 carbon atoms; and each of the aforesaid alkanoyl moieties having 2 to 4 carbon atoms.

2. Chemical compounds having the formula:

in which A is an alkylene chain having 2 to 6 carbon atoms, separating the nitrogens to which it is attached by at least 2 carbon atoms; and the alkyl moieties have 1 to 4 carbon atoms.

3. A chemical compound having the formula:

CHgCHgCHr-N 4. Chemical compounds having the formula:

in which A is an alkylene chain having 2 to 6 carbon atoms, separating the nitrogens to which it is attached by at least 2 carbon atoms; and the alkyl moiety has 1 to 4 carbon atoms.

5. A chemical compound having the formula:

6. Chemical compounds having the formula:

CH CH CHg- N-alkyleue-hydroxy in which the alkylene moiety has 2 to 4 carbon atoms.

7. A chemical compound having the formula: 

1. CHEMICAL COMPOUNDS OF THE CLASS CONSISTING OF A FREE BASE AND ITS NONTOXIC ORGANIC AND INORGANIC ACID SALTS, THE FREE BASE HAVING THE FORMULA: 